Process for the production of 3-vinyl cephalosporins

ABSTRACT

A process for the production of a 3-vinylcephalosporin compound of formula I                    
     wherein R 1  and R 2  denote hydrogen or an organic group by a Wittig reaction reacting first a compound of formula II                    
     with a compound of formula P(R 4 ) 3  or P(OR 4 ) 3  to produce a compound of formula III                    
     and secondly reacting the compound of formula III with a weak base of formula                    
     or of formula R 10 —COO − W +   
     wherein 
     R 5  is hydrogen, alkly or aryl and R 6  and R 7  are each an activated group of formula —COOR 8 , —CN, —SO 2 R 8 , —COR 8  or —CON(R 8 ) 2 ; or 
     R 5  and R 8  are each aryl and R 7  is an activated group of formula —COOR 8 , —CN, —SO 2 R 8 , —COR 8  or —CON(R 8 ) 2 , W +  is an alkali metal cation and R 10  is alkyl or aryl 
     to produce a compound of formula IV                    
     and finally reacting a compound of formula IV with a compound of formula V                    
     to produce a compound of formula I.

This is a continuation of U.S. application Ser. No. 08/829,572, U.S.Pat. No. 6,248,881 filed Mar. 31, 1997, which is a continuation of U.S.application Ser. No. 08/149,431, filed Nov. 9, 1993, now abandoned,which is a continuation-in-part of U.S. application Ser. No. 08/069,239,filed May 28, 1993, now U.S. Pat. No. 5,401,841, which is a continuationof U.S. application Ser. No. 07/848,457, filed Mar. 9, 1992, nowabandoned.

The invention relates to an economical and simple process for theproduction of 3-vinylcephalosporin compounds of formula I

wherein R₁ and R₂ may be the same or different and denote hydrogen or anorganic radical.

The compounds of formula I are known to be useful starting products forthe production of valuable 3-substituted vinyl cephalosporins.

In substituents R₁ and R₂, the organic radical may signify for examplean optionally branched alkyl, alkenyl or alkinyl group; a totally orpartially saturated cycloalkyl radical; or an optionally substitutedaryl radical, aralkyl radical or heterocycle. The cycloalkyl radical,aryl radical, aralkyl radical or heterocycle may be substituted in anyposition, for example by halogen, nitrogen, sulphur, alkoxy, aryloxy, ora functional group such as a carbalkoxy or carboxamido group. R₁ and R₂may also form part of an optionally substituted ring system.

In a preferred embodiment of the invention one of R₁ and R₂ is hydrogenand the other is:

i) hydrogen, lower alkyl, lower alkenyl, or lower alkinyl;

ii) lower cycloalkyl, lower cycloalkyl lower alkyl, aryl, (aryl)-loweralkyl, a heterocyclic group or a heterocyclyl-(lower)-alkyl, the ring ofeach of which may be optionally substituted by 1 to 3 lower alkoxy,lower alkylthio, halogen, lower alkyl, nitro, hydroxy, acyloxy, carboxy,carbalkoxy, lower alkylcarbonyl, lower alkylsulfonyl, loweralkoxysulfonyl, amino-(lower)-alkyl amino or acylamido groups; or

iii) a group of formula —CH₂Z, in which Z is a) hydroxy, lower alkoxy,formyloxy, acetyloxy, lower alkylsulfonyloxy, halogen,N-mono(lower)alkylcarbamoyloxy, or N,N-di(lower)alkylcarbamoyloxy; b) aheterocyclic group; c) a group of formula —S(O)_(m)R₉ in which R₉ is analiphatic, araliphatic, alicyclic, aromatic or heterocyclic group, and mis 0, 1 or 2; or d) an acyclic or cyclic ammonium group.

Suitable heterocyclic groups include single or fused heterocyclic ringshaving 4 to 7, preferably 5- or 6-atoms in each ring. Each ring has upto four hetero atoms in it selected from oxygen, nitrogen and sulphur.Also each heterocyclic ring may have 1 to 3 optional substituentsselected from (C₁₋₄) alkyl, (C₁₋₄) alkoxy, halogen, trihalo-(C₁₋₄)alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C₁₋₄)alkylamino, carboxymethyl, carbamoylmethyl, sulfomethyl andmethoxycarbonylamino.

Examples of suitable heterocycle rings include unsubstituted andsubstituted imidazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, triazolylpyridyl, purinyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl.

Preferably, suitable heterocycle rings include unsubstituted andsubstituted 5-hydroxy-4-pyridon-2-yl, 1,2,3-triazolyl; 1,2,4-triazolyl;tetrazolyl; oxazolyl; thiazolyl; 1,3,4-oxadiazolyl; 1,3,4-thiadiazolylor 1,2,3-thiadiazolyl. Preferably the heterocycle is1,5-dihydroxy-4-pyridon-2-yl, 5-hydroxy-1-methyl-4-pyridon-2-yl,5-hydroxy-4-pyridon-2-yl, 1-methyl- 1H-tetrazol-5-yl-2-methyl-1,3,4-thiadiazol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl,6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-yl, 1,2,3 -triazol-5-yl, and4-methyl-thiazol-5-yl.

Examples of acyclic ammonium groups include(1-carbamoyl-2—(carbamoylmethyl)(ethyl)-methylammonium or trimethylammonium.

Examples of cyclic ammonium groups are pyrrolidinium, which isN-substituted by alkyl, carbamoylalkyl, aminoalkyl or carboxyalkyl;pyridinium or cyclopentenopyridinium, which may be mono- ordi-substituted by alkyl, halogen, hydroxy, carboxamido, alkoxycarbonyl,amino, monoalkylamino or dialkylamino.

Except where otherwise indicated, the organic radicals preferablycontain up to 10 carbon atoms and “lower” means the group has up to 4carbon atoms.

Processes for the production of compounds of formula I are known and arediscussed in EP 0503453, the disclosure of which is incorporated byreference. However, as discussed in EP 0503453, these known processesrequire the use of expensive protection groups and require amultiplicity of intermediate stages. The invention disclosed in EP0503453 addressed the problems of the prior art by making use of silylprotection groups in a Wittig reaction using 7-amino cephalosporanicacid as starting reagent.

The process disclosed in EP 0503453 proceeds according to the followingreaction scheme:

i) a compound of the formula II

in which R is a silyl protecting group, is reacted with a compound ofthe formula P(R₄)₃ or P(OR₄)₃ to produce a compound of formula III

in which X is —P(R₄)₃.I or —P(O).(OR₄)₂, R is as defined above and R₄ isa lower alkyl group or an aryl group;

ii) the compound of the formula III is then reacted with a strong baseto produce a compound of the formula IV

in which X⁺ is —P⁺(R₄)₃ or —P(O).(OR₄)₂.Y, R₄ and R are as defined aboveand Y is a cation of the alkali series or the protonated form of astrong organic base; and

iii) the compound of the formula IV is reacted with a compound of theformula V

in which R₁ and R₂ are as defined above, to produce the compound of theformula I. The resulting process is simple, economical and may becarried out in a single reaction vessel. Also, it has the advantage thatthe silyl protection groups are removable by simple hydrolysis oralcoholysis.

The base used in step ii) is a strong organic base and guanidines (forexample tetramethylguanidine), amidines (for example1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicylo[4.3.0]non-5-ene),alkali salts of nitrogen-containing compounds (for example the Li or Nasalts of 1,1,1,3,3,3-hexamethyldisilazane and Li-diisopropylamide),butyllithium, hydrides of alkali metals, and iminophosphoranes are givenas suitable examples. It is also mentioned that the bases should be freeof moisture and should not contain any parts that could be silylated, soas to maintain the degree of silylation of the product.

It has now been surprisingly found that the process described in EP0503453 may be carried out using weaker bases. This is of particularadvantage since the reaction may be carried out under milder conditions.

Therefore this invention provides a process, substantially as definedabove, for the production of a compound of formula I which is improvedby the use of a weak base in step ii).

That a weaker base could be used in a Wittig reaction is indeedsurprising. The use of the weaker base has the advantage that thepossibility of opening the β-lactam ring is reduced and superfluouscondensation of the base with the aldehyde or ketone is avoided orrestricted.

Preferably the weak base is such that its conjugate acid has asilylatable function and the reaction step ii) is carried out in thepresence of a silylating agent to cause silylation of the silylatablefunction. Surprisingly, the reaction proceeds without the silylprotecting group on the 7-amino group, which is a very potent silylatingagent and which is easily removed, being removed by the base orconjugate acid. If the silyl protecting group were to be removed duringthe reaction, the amino group would be free to react with the aldehydeor ketone of formula V and this would cause the reaction to collapse.

Preferably the weak base is selected from:

i) compounds that have the formula

in which R₅ is hydrogen, alkyl or aryl; R₆ and R₇, which may be the sameor different, are each an activated group of the formula —COOR₈, —CN,—SO₂R₈, —COR₈ or —CON(R₈)₂; or R₅ and R₆, which may be the same ordifferent, are each aryl and R₇ is an activated group of the formula—COOR₈, —CN, —SO₂R₈, —COR₈ or —CON(R₈)₂; W⁺ is a cation (for examplelithium, sodium, or calcium); and R₈ is alkyl, cycloalkyl or aryl; and

ii) salts of carboxylic acids of the formula R₁₀—COO⁻ W⁺ in which R₁₀ isan optionally branched alkyl group or an optionally substituted arylgroup; and W⁺ is as defined above.

Particularly preferred weak bases are lithium and sodium salts ofmalonic acid diethyl esters, acetoacetic acid esters, acetic acid,pivalic acid, or ethylhexanoic acids, or lithium salts of benzoic acids.

The silylating agent may be added to the reaction mixture prior to theaddition of the weak base or simultaneously with the weak base; in bothcases to cause the silylation of silylatable function of the conjugateacid of the weak base. N,O-bis(trimethylsilyl)-acetamide andbissilylurea are particularly suitable as silylating agents and furtherexamples are given in EP 0503453.

The reaction may be carried in a suitable solvent or solvent mixturewhich is inert under the reaction conditions, for example an inert ether(such as tetra-hydrofuran, diethyl ether, an ethylene glycol dialkylether or a tert.butylmethyl ether), an inert amide (such asdimethylformamide, dimethylacetamide or N-methylpyrrolidone), an urea(such as tetra-methylurea,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, or1,3,2-imidazolidinone) a nitrile (such as acetonitrile), or ahalogenated hydrocarbon (such as dichloromethane).

Should a substituent of the aldehyde or the ketone of formula V containa function which is easily silylated, this should be blocked temporarilywith an appropriate silylation agent prior to the reaction. The amountof the compound of formula V may be stoichiometrical or in excess basedon the amount of the compound of formula IV.

The reaction may be carried out over a wide temperature range,preferably at a temperature of between −70° C. and +70° C.

The compounds of formula I may be isolated in a conventional manner. Thesilyl protecting groups may be removed by simple hydrolysis oralcoholysis. This may be done either by adding the desilylation agent tothe reaction mixture, or by extracting the product into a separableaqueous phase, adding water (under alkaline or acidic conditions) andprecipitating by adjusting the pH value to the isoelectric point,optionally adding an organic solvent.

The compounds of formula II are known and may be produced as describedin EP 0503453.

The compounds of formula I are important starting materials for theproduction of valuable cephalosporin antibiotics. Cephalosporins whichare vinyl-substituted in 3-position are either resorbed orally, or whenadministered parenterally, are characterized for their very broad,efficient spectrum of activity. The following compounds may be producedfor example:

In the following examples, which illustrate the invention more fully,but in no way limit its scope, all temperatures are given in degreescelsius.

EXAMPLE 1 7-Amino-3-(3-acetoxy-1-propenyl)-3-cephem-4-carboxylic acid

7.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml of adichloromethane solution containing 6 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide on ice. 25 ml of a N-Methylpyrrolidonesolution, at 5 to 10°, containing 2.35 g sodium aceto-acetic acid ethylester, is added dropwise. The dark red solution is then cooled to 2° and5.16 g acetoxyaldehyde is added dropwise. The reaction mixture is thenstirred for 2 hours at 10° and then added to a mixture of 100 ml aceticacid and 100 ml water. The pH of the aqueous phase is adjusted to 7 withammonia and the organic phase is separated off. The pH is adjusted to3.5 by adding 1:1 diluted concentrated HCl, whereupon the title compoundprecipitates. The suspension is stirred for 30 minutes at 5°, the titlecompound is filtered off, washed in acetone and dried.

EXAMPLE 2 7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid

5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml of adichloromethane solution containing 6 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide on ice. 25 ml of a N-Methylpyrrolidonesolution, at 5 to 10°, containing 2.35 g sodium malonic acid diethylester, is added dropwise. Thereafter the solution is cooled to −10° and1.32 g acetaldehyde, dissolved in 10 ml dichloromethane, is added. Afterthe addition of the acetaldehyde, the reaction mixture is stirred for 48hours at 0°. Thereafter the process proceeds as described in example 1.

EXAMPLE 3 7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid

36.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 500 ml of adichloromethane solution containing 24 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide at a temperature of −10°. A suspensionof 12.8 g lithium benzoate in 75 ml N-Methylpyrrolidone is added. 9 g ofacetaldehyde is added and the reaction mixture is stirred for 2 days at0°. Superfluous acetaldehyde and most of the dichloromethane are removedin a rotary evaporator. The residue is then stirred in 1500 ml of waterand then filtered. The residue is dissolved in 200 ml aqueous ammoniaand the aqueous phase is extracted twice using 100 ml dichloromethane.After removal of the organic phase, 1:1 diluted concentrated HCl isadded to the aqueous phase to bring the pH to 3.5 whereupon the titlecompound precipitates. The suspension is stirred for 30 minutes at 50°,the title compound is filtered off, washed in acetone and dried.

EXAMPLE 4 7-Amino-3-(3-acetoxy-1-propen-1-yl)-3-cephem-4-carboxylic acid

7.5 ml of N,O-bis(trimethylsilyl)acetamide is added to 25 ml of adichloromethane solution containing 6 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide on ice. 15 ml of a N-methylpyrrilidonesolution containing 2.5 g sodium-ethylhexanoate is added dropwise at 0to 5°. 5 ml of acetoxy-acetaldehyde is added dropwise. The reactionmixture is stirred overnight at 0° and then processed as described inexample 1.

EXAMPLE 57-Amino-3-[2-(4-methyl-5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid

25 g of a dichloromethane solution containing 10.2 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide is cooled to a temperature of −10°. 4.7ml of N,O-bis(trimethylsilyl)acetamide, 11 ml dimethylformamide and 1.1g lithium acetate are added and the mixture stirred at 0 to 5° for 30minutes. A solution of 2 g of 4-methyl-thiazol-5-carboxyaldehyde in 5 mldichloromethane is then added dropwise. The mixture is then stirred for10 hours at 30°, cooled to 10° and stirred for a further hour at 10°.The title compound is separated using a suction filter, washed withmethanol and vacuum dried.

EXAMPLE 6 7-Amino-3-(prop-1-enyl)-3-cephem-4-carboxylic acid

220.7 g of a dichloromethane solution containing 68.7 g of7-trimethylsilylamino-3-triphenyl-phosphoniummethyl-3-cephem-4-carboxylicacid trimethylsilylester-iodide is cooled to a temperature of −10°. 58.4ml of N,O-bis(trimethylsilyl)acetamide and 81 ml N,N-dimethylacetamideis added while stirring. A solution of 14.05 g lithium pivalate is addedand the mixture stirred for 30 minutes at −10°. 17.2 ml of acetaldehydeis added and the reaction mixture is stirred for 90 minutes at −10° andthen overnight at 0°. Superfluous acetaldehyde and some of thedichloromethane are removed in a rotary evaporator under vacuum and at20°. The residue is then stirred into 500 ml of ice-cold water and 100ml dichloromethane. The pH value is adjusted to 8.5 with aqueousammonia. The phases are then separated and the aqueous phase is washedwith 100 ml dichloromethane and combined with 200 ml acetone. The pH isadjusted to 3.5 with 1:1 diluted concentrated hydrochloric acid at 30°to precipitate the title compound. The suspension is held in the icebath for 2 hours whilst stirring, and the title compound is isolatedusing a suction filter. The title compound is washed with a mixture of100 ml of water and 50 ml acetone and then again with 50 ml of acetone.The title compound is then dried in a vacuum drying chamber at 40°.

What is claimed is:
 1. A process for the production of a3-vinylcephalosporin compound of formula I

wherein R₁ and R₂ may be the same or different and denote hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl wherein C—C bonds areunsaturated, aryl, aralkyl, or heterocyclyl, selected from unsubstitutedand substituted imidazolyl, diazolyl, trialzolyl, tetrazolyl, thiazolyl,thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, triazolopyridyl, purinyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl, wherein theheterocycle may be unsubstituted or substituted by (C₁₋₄) alkyl, (C₁₋₄)alkoxy, halogen, trihalo-(C₁₋₄) alkyl, hydroxy, mercapto, amino,carboxyl, carbamoyl, di-(C₁₋₁₄) alkylamino, carboxymethyl,carbamoylmethyl, sulfomethyl or methoxycarbonylamino, said processcomprising the steps of i) reacting a compound of formula II

in which R is a silyl protecting group, with a compound of the formulaP(R₄)₃ or P(OR₄)₃ to produce a compound of formula III

wherein X is —P(R₄)₃I or —P(O)(OR₄)₂, R is as defined above, and R₄ is a(C₁₋₄)alkyl group or an aryl group containing up to 10 carbon atoms; ii)reacting the compound of formula III with a base to produce a compoundof formula IV

wherein X⁺ is —P⁺(R₄)₃ or —P(O).(OR₄)₂Y⁺, R₄ and R are as defined aboveand Y⁺ is an alkali metal cation; and iii) reacting a compound offormula IV with a compound of formula V

wherein R₁ and R₂ are as defined above, and splitting off the silylprotecting group R, to produce a compound of formula; the improvementwhich comprises that the base in step ii) is a weak base selected from:i) a compound formula

wherein R₅ is hydrogen, (C₁₋₁₀) alkyl or aryl containing up to 10 carbonatoms and R₆ and R₇, which may be the same or different, are each anactivated group of formula —COOR₈, —CN, —SO₂R₈, —COR₈ or —CON (R₈)₂; orR₅ and R₆, which may be the same or different, are each aryl containingup to 10 carbon atoms and R₇ is an activated group of formula —COOR₈,—CN, —SO₂R₈, —COR₈ or —CON(R₈)₂; W⁺ is an alkali metal cation; and R₈ is(C₁₋₁₀) alkyl, cycloalkyl or aryl containing up to 10 carbon atoms; orii) a salt of a carboxylic acid of formula R₁₀—COO⁻W³⁰ in which R₁₀ is(C₁₋₁₀)alkyl or aryl containing up to 10 carbon atoms; and W⁺ is definedabove, with a compound of formula III in step ii).
 2. A process for theproduction of a 3-vinylcephalosporin compound of formula I

wherein R₁ and R₂ may be the same or different and denote hydrogen,(C₁₋₁₀)alkyl, (C₁₋₁₀)alkenyl, (C₁₋₁₀)alkynyl, cycloalkyl, cycloalkylwherein C-C bonds are unsaturated, (C₁₋₁₀)aryl, (C₁₋₁₀)ralkyl, or asingle or fused heterocyclic ring selected from unsubstituted andsubstituted imidazolyl, diazolyl, triaxolyl, tetrazolyl, thiazolyl,thiadiazolyl, thiatriazolyl, oxayolyl, oxadiazolyl, benzimidazolyl,b3nzoxazolyl, benzothiazolyl, triaszolopyridyl, purinyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazolyl and triazinyl, wherein theheterocycle may be unsubstituted or substituted by (C₁₋₄) alkyl, (C₁₋₄)alkoxy, halogen, trihalo-(C₁₋₄) alkyl, hydroxy, mercapto, amino,carboxyl, carbamoyl, di-(C₁₋₄) alkylamino, carboxymethyl,carbamoylmethyl, sulfomethyl or methoxycarbonylamino, said processcomprising the steps of i) reacting a compound of formula II

in which R is a silyl protecting group, with a compound of formulaP(R₄)₃ or P(OR₄)₃ to produce a compound of formula III

wherein X is —P(R₄)₃ I or —P (O) (OR₄)₂, R is as defined above, and R₄is a (C₁₋₄)alkyl group or an aryl group containing up to 10 carbonatoms; reacting the compound of formula III with a base to produce acompound of formula IV

wherein X³⁰ is —P⁺(R₄)₃ or —(O)(OR₄)₂Y^(+,) R₄ and R are as definedabove and Y⁺is an alkali metal cation; and iii) reacting a compound offormula IV with a compound of formula V

wherein R₁ and R₂ are as defined above, and splitting off the silylprotecting group R, to produce a compound of formula I; the improvementwhich comprises that the base in step ii) is a weak base selected from:i) a compound of formula

wherein R₅ is hydrogen, (C₁₋₁₀)alkyl or aryl containing up to 10 carbonatoms and R₆ and R₇, which may be the same or different, are each anactivated group of formula —COOR₈, —CN, —SO₂R₈, —COR₈ or —CON(R₈)₂; orR₅ and R₆, which may be the same or different, are each aryl containingup to 10 carbon atoms and R₇ is an activated group of formula —COOR₈,—CN, —SO₂R₈, —COR₈ or —CON(R₈)₂; W⁺is an alkali metal cation; and R₈ is(C₁₋₁₀)alkyl, cycloalkyl or aryl containing up to 10 carbon atoms; orii) a salt of a carboxylic acid of formula R₁₀—COO⁻W⁺ is as definedabove, with a compound of formula III in step ii).
 3. A processaccording to claim 1 in which the conjugate acid of the weak base ofstep ii) has an easily silylatable function and the reaction of step ii)is carried out in the presence of a silylating agent.
 4. A processaccording to claim 2 in which the conjugate acid of the weak base ofstep ii) has an easily silylatable function and the reaction of step ii)is carried out in the presence of a silylating agent.
 5. A processaccording to claim 1 in which the weak base is a lithium or sodium saltof malonic acid diethyl ester, acetoacetic acid ester, acetic acid,pivalic acid, or ethylhexanoic acid, or is a lithium salt of benzoicacid.
 6. A process according to claim 2 in which the weak base is alithium or sodium salt of malonic acid diethyl ester, acetoacetic acidester, acetic acid, pivalic acid, or ethylhexanoic acid, or is a lithiumsalt of benzoic acid.
 7. A process according to claim 3 in which thesilylating agent is added to the reaction mixture prior to the additionof the weak base.
 8. A process according to claim 4 in which thesilylting agent is added to the reaction mixture prior to the additionof the weak base.
 9. A process according to claim 3 in which thesilylating agent is added to the reaction mixture at the same time asthe weak base.
 10. A process according to claim 4 in which thesilylating agent is added to the reaction mixture at the same time asthe weak base.
 11. A process according to claim 3 in which thesilylating agent is N,O-bis(trimethylsilyl)acetamide or bissilylurea.12. A process according to claim 4 in which the silylting agent isN,O-bis-trimethylsilyl)acetamide or bissilylurea.